Behavioral studies of aging monkeys reveal cognitive impairments that are likely to reflect neuronal dysfunction in the prefrontal cortex and temporal lobe limbic system. Yet there is no overt loss of neurons with age in either area. We have also demonstrated that there is no major loss of synapses in the molecular layer of the dentate gyrus and that basic membrane properties of these granules cells are preserved with age. This subtle, sublethal in neuronal function must occur and we have evidence for several including changes in a number of neurotransmitter receptors and decreases in markers of oxidative metabolism. Other studies by colleagues have demonstrated degenerative changes in myelin. A principal question is whether these changes reflect damage or are compensatory responses. For example, principal question is whether these changes reflect damage or are compensatory responses. For example, neurotransmitter receptor loss could simply reflect degenerative changes in dendrites while receptor increase or changes in affinity might be a compensatory response resulting from altered patterns of synaptic input caused by myelin damage. We will investigate these issues using a physiological and morphological methods to characterize neurons in the hippocampus and neocortex according to the following specific aims. First, we will use the in vitro slice preparation to identify alterations in neuronal physiology and synaptic function of the major neurotransmitter systems. Second, we will simultaneously fill these neurons with biocytin and reconstruct their dendrites and spines. Third, we will determine if a quantitative autoradiographic assessment of changes in myelination. Fourth, we will determine if changes in neurotransmitter receptors are a compensatory response are a compensatory response by using in situ hybridization to identify altered gene expression. And finally we will identify the distribution and extent of impaired oxidative metabolism and its relationship to other sublethal changes described above. Our goal is to identify the major age-related functional changes in neurons of these critical areas. These studies will be conducted in young adult, middle aged and elderly rhesus monkeys that have been behaviorally characterized. By examining these issues for the first time in late middle aged monkeys we will be able to determine which of these functional impairments appears first during normal aging.